CALR is the soluble ER-luminal paralog of calnexin, one of the two central ER lectin
chaperones of the calnexin/calreticulin (CNX/CRT) cycle. It binds monoglucosylated
N-glycans (Glc1Man9GlcNAc2) on nascent glycoproteins, recruits ERp57 (PDIA3) for
oxidative folding, retains/triages misfolded glycoproteins for ER quality control,
and is a major high-capacity Ca2+-binding protein that regulates ER calcium storage.
It is a key chaperone in MHC class I peptide loading. Beyond the ER, CALR has
well-documented secondary roles: a cell-surface/extracellular "eat-me" signal driving
immunogenic cell death and phagocytosis, and a variety of context-specific reported
functions (integrin cytoplasmic-tail binding, nuclear-export receptor for steroid
receptors, transcriptional/translational modulation).
UniProt FUNCTION [file:human/CALR/CALR-uniprot.txt]:
"Calcium-binding chaperone that promotes folding, oligomeric assembly and quality
control in the endoplasmic reticulum (ER) via the calreticulin/calnexin cycle. This
lectin interacts transiently with almost all of the monoglucosylated glycoproteins
that are synthesized in the ER".
Review [PMID:15474971 "Calreticulin is a 46-kDa Ca2+-binding chaperone found across a
diverse range of species. The protein is involved in the regulation of intracellular
Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity. Calreticulin is
also an important molecular chaperone involved in "quality control" within secretory
pathways."]. This review supports the calcium-binding, chaperone, and quality-control
core functions (TAS-grade synthesis source).
Lectin/glycan binding: CALR binds monoglucosylated MHC I glycans; PMID:15056662 Carbohydrate
binding (GO:0030246) is a core MF.
MHC class I peptide loading complex (PLC): CALR is a structural component of the PLC
and supports peptide-receptive MHC I. PMID:35948544 CALR-null cells have impaired MHC I
assembly [PMID:11825569 title]. This is a specialized but well-supported application of
the core chaperone function; I treat PLC membership / peptide antigen assembly as
core-adjacent (ACCEPT for the direct IDA in the human PLC structure paper, KEEP_AS_NON_CORE
for ISS transfers).
Client chaperone examples: insulin receptor PMID:17563366. Mutant CALR perturbs the glycoproteome PMID:36417879.
Numerous IPI "protein binding" annotations from interactome maps and individual partner
studies (HLA-F/HLA-E, GABARAP, MBL, ERp57, etc.). Per guidelines, bare "protein binding"
is uninformative -> MARK_AS_OVER_ANNOTATED.
The Falcon report (CALR-deep-research-falcon.md) overwhelmingly CONFIRMS the existing
review for canonical biology (ER-luminal lectin chaperone of the CNX/CRT cycle, binds
monoglucosylated N-glycans, recruits ERp57/PDIA3 via the P-domain, high-capacity/low-affinity
ER Ca2+ buffer, KDEL retrieval, ecto-CALR eat-me/ICD role). The genuinely NEW material is the
oncogenic exon 9 mutant-CALR / MPN axis, which is entirely absent from the existing
existing_annotations (correctly, since these are neomorphic disease mutations not in GOA),
plus a more explicit receptor mechanism for the eat-me signal. Key points:
NEW (disease, well established): Somatic exon 9 frameshift (+1 bp) CALR mutations are driver
lesions in JAK2/MPL-nonmutated myeloproliferative neoplasms (essential thrombocythemia,
primary myelofibrosis), replacing the acidic Ca2+-binding C-terminus + KDEL with a shared
novel basic tail. First described in two 2013 NEJM papers [PMID:24325356 "Somatic insertions
or deletions in exon 9 of CALR"; PMID:24325359 "Mutations were located in exon 9 and
generated a +1 base-pair frameshift"]. Type 1 (del52) and type 2 (ins5) ~80% of mutant cases.
This is mutation biology, not a function of WT CALR -> does NOT alter existing_annotations;
recorded here and as statement-only references for context.
NEW (mechanism): Mutant CALR gains a neomorphic, ligand(TPO)-independent interaction with the
thrombopoietin receptor MPL (N-domain recognition of MPL N-glycans plus the mutant basic
C-terminus), driving constitutive JAK2/STAT5(3), ERK1/2 and AKT activation and megakaryocytic
transformation; MPL is required [PMID:27177927 Han 2016 "Exogenous expression of MPL led to
constitutive activation of STAT3 and 5, ERK1/2, and AKT, cytokine-independent growth"]. Mutant
CALR also shows accelerated degradation and Golgi-mediated secretion (same paper).
NEW (mechanism, ties to Ca2+ core): Type 1 (but not type 2) mutants lose more acidic
Ca2+-binding residues, directly impairing Ca2+ binding -> ER Ca2+ depletion -> selective
activation of the IRE1alpha/XBP1 UPR arm; IRE1alpha/XBP1 inhibition selectively kills type 1
mutant cells in vivo [PMID:35405004 Ibarra 2022 "loss of Ca2+ binding residues in the type I
mutant CALR protein directly impairs its Ca2+ binding ability...activation of the IRE1alpha/XBP1
pathway"]. Mechanistically links the WT high-capacity Ca2+-buffer function to disease.
CONFIRMS + refines (interaction/pathway): ecto-CALR drives pro-phagocytic clearance via the
LRP1/CD91 receptor on phagocytes/APCs (the existing review notes phagocytosis/eat-me and SCARF1/
MSR1 scavenger receptors but not LRP1/CD91 by name). Falcon supports this only via 2024 review
sources (janssens2024, reid/galassi2024), not primary data -> treat as PROVISIONAL receptor
detail; not used to change annotations. GO:0050766 (positive regulation of phagocytosis) already
KEEP_AS_NON_CORE.
CONFIRMS (translational, not GO-actionable): mutant-CALR neo-C-terminus is a cell-surface
neoantigen; active immunotherapy programs (peptide vaccine NCT05025488; bispecific JNJ-88549968
NCT06150157) and antibody efforts (kramer2024 review). Context only; no annotation impact.
Provenance caveats: Falcon's quantitative MPN prevalence figures vary across sources
(~20% MPN / ~25-30% ET / ~40% ET+PMF) due to different denominators; the Faiz 2023 source is a
thesis ("Unknown journal") and reid2024 has 0 citations -> low-confidence, kept out of the YAML.
Only the four primary/peer-reviewed PMIDs above were resolved (via PubMed) and added as
statement-only references.